Medicament injection device

ABSTRACT

A medicament injection device comprising a main body arranged to receive a medicament cartridge; a needle carrier carrying a needle, wherein the needle carrier is axially movable with respect to the main body; and a rotatable cap at a distal end of the device, wherein the cap is removably coupled to the needle carrier, a releasable arrangement between the main body and the cap comprising a guide element and a slotted link, wherein the slotted link is arranged to cause the guide element to follow a predefined path at least partly in an axial direction during rotational movement of the cap, thereby causing the needle carrier to move axially towards a proximal end of the device as the cap is rotated up to a predefined point, wherein the main body comprises a medicament cartridge holder comprising the guide element depending therefrom for engagement with the cap.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is the national stage entry of InternationalPatent Application No. PCT/EP2016/078274, filed on Nov. 21, 2016, andclaims priority to Application No. EP 15196709.8, filed in on Nov. 27,2015, the disclosures of which are incorporated herein by reference.

TECHNICAL FIELD

The present disclosure relates to a medicament injection device.

BACKGROUND

Medicament injection devices can take various forms. One form uses asyringe, where medicament is stored in a hollow cylinder, typicallyformed of glass. The medicament is sealed from the environment with aplunger moveable within the cylinder, and a needle fluidly connected tothe syringe's distal end. The needle must remain capped in order tomaintain the medicament under sterile conditions.

Another form of injection device uses a cartridge instead of a syringe,the cartridge having a distal seal instead of the syringe's needle.Typically a patient connects a double-ended needle to the cartridgebefore injection, thereby piercing the cartridge's seal with theproximal tip of the double-ended needle.

While a cartridge can provide handling and storage advantages relativeto syringes, they are not without shortcomings. For example, theattachment of a needle to the cartridge requires an additional step.This step can be problematic for patients with limited dexterity, poorcoordination, or who have lost a degree of sensation in their hands.Even with such disadvantages, in certain situations it is desirable toprovide an injection device in which the needle is kept separate fromthe medicament until such time as the patient wishes to commence theinjection.

SUMMARY

A first embodiment provides a medicament injection device comprising amain body arranged to receive a medicament cartridge; a needle carriercarrying a needle, wherein the needle carrier is axially movable withrespect to the main body; and a rotatable cap at a distal end of thedevice, wherein the cap is removably coupled to the needle carrier, areleasable arrangement between the main body and the cap comprising aguide element and a slotted link, wherein the slotted link is arrangedto cause the guide element to follow a predefined path at least partlyin an axial direction during rotational movement of the cap, therebycausing the needle carrier to move axially towards a proximal end of thedevice as the cap is rotated up to a predefined point, wherein the mainbody comprises a medicament cartridge holder comprising the guideelement depending therefrom for engagement with the cap.

The cap may comprise a tubular element, the outer surface of the tubularneedle shielding element having the slotted link arranged thereon toreceive the guide element.

The tubular element may contain a needle shield.

The slotted link may be configured to cause the cap to move axially in adistal axial direction when the cap is rotated beyond the predefinedpoint.

The slotted link may comprise a portion that is relatively narrow incomparison to the remainder of the slotted link.

The slotted link may comprises an axially straight part.

The needle holder may be arranged to become fixed to the medicamentcartridge after axial movement thereof in the proximal direction.

The needle holder may comprise a lip arranged to cooperate with a headof the medicament cartridge.

The needle holder may be dimensioned to form a frictional fit with thehead of the medicament cartridge.

The medicament cartridge holder may contain a medicament cartridgehaving a penetrable barrier at a distal end thereof, and the axialmovement of the needle carrier towards the proximal end may cause theneedle to pierce the barrier of the medicament cartridge.

The medicament cartridge may contain a medicament.

The device may be an auto-injector.

A second embodiment provides a method of operating a medicamentinjection device having a rotatable cap, the method comprising: rotatingthe cap, thereby causing a releasable arrangement between the main bodyand the cap comprising a guide element and a slotted link to cooperateto cause a needle to move axially in a proximal direction and topenetrate a separable barrier of a medicament cartridge.

Further rotation of the cap may cause the cap to move axially in adistal direction.

BRIEF DESCRIPTION OF THE FIGURES

Exemplary embodiments of the present disclosure are described withreference to the accompanying drawings, in which:

FIGS. 1A and 1B are side-on views of an auto-injector device accordingto embodiments of the disclosure;

FIG. 2A is a side-on cross sectional schematic view of a device having acap according to a first embodiment before the cap is rotated;

FIG. 2B is a representation of the engagement of a guide element with aslotted link in the device shown in FIG. 2A;

FIG. 3A is a side-on cross sectional schematic view of the device of thefirst embodiment as the cap is rotated;

FIG. 3B is a representation of the engagement of the guide element withthe slotted link in the device shown in FIG. 3A;

FIG. 4A is a side-on cross sectional schematic view of the device of thefirst embodiment as the cap is being removed;

FIG. 4B is a representation of the engagement of the guide element withthe slotted link in the device shown in FIG. 4A; and

FIG. 5 shows a narrowing of a slotted link.

DETAILED DESCRIPTION

Embodiments provide a mechanism for inserting the needle of an injectiondevice such as an auto-injector or syringe into a medicament cartridgecontaining the medicament to be injected. Providing such a mechanismallows the medicament cartridge to be sealed until such time as the userwishes to commence the injection. Providing an automated mechanism forinserting the needle into the medicament cartridge also reduces theamount of handling of the needle by the user prior to the injection.Indeed, in embodiments the user does not need to touch the needle duringthe steps of inserting the needle into the medicament cartridge andsubsequently actuating the injection of the medicament.

Embodiments provide a mechanism whereby a needle holder holding a needleis automatically connected to a medicament cartridge in response torotation of a device cap.

A drug delivery device, as described herein, may be configured to injecta medicament into a patient. For example, delivery could besub-cutaneous, intra-muscular, or intravenous. Such a device could beoperated by a patient or care-giver, such as a nurse or physician, andcan include various types of safety syringe, pen-injector, orauto-injector. The device can include a cartridge-based system thatrequires piercing a sealed ampule before use. Volumes of medicamentdelivered with these various devices can range from about 0.5 ml toabout 2 ml. Yet another device can include a large volume device (“LVD”)or patch pump, configured to adhere to a patient's skin for a period oftime (e.g., about 5, 15, 30, 60, or 120 minutes) to deliver a “large”volume of medicament (typically about 2 ml to about 10 ml).

In combination with a specific medicament, the presently describeddevices may also be customized in order to operate within requiredspecifications. For example, the device may be customized to inject amedicament within a certain time period (e.g., about 3 to about 20seconds for auto-injectors, and about 10 minutes to about 60 minutes foran LVD). Other specifications can include a low or minimal level ofdiscomfort, or to certain conditions related to human factors,shelf-life, expiry, biocompatibility, environmental considerations, etc.Such variations can arise due to various factors, such as, for example,a drug ranging in viscosity from about 3 cP to about 50 cP.Consequently, a drug delivery device will often include a hollow needleranging from about 25 to about 31 Gauge in size. Common sizes are 27 and29 Gauge.

The delivery devices described herein can also include one or moreautomated functions. For example, one or more of needle insertion,medicament injection, and needle retraction can be automated. Energy forone or more automation steps can be provided by one or more energysources. Energy sources can include, for example, mechanical, pneumatic,chemical, or electrical energy. For example, mechanical energy sourcescan include springs, levers, elastomers, or other mechanical mechanismsto store or release energy. One or more energy sources can be combinedinto a single device. Devices can further include gears, valves, orother mechanisms to convert energy into movement of one or morecomponents of a device. The one or more automated functions of anauto-injector may each be activated via an activation mechanism. Such anactivation mechanism can include one or more of a button, a lever, aneedle sleeve, or other activation component. Activation of an automatedfunction may be a one-step or multi-step process. That is, a user mayneed to activate one or more activation components in order to cause theautomated function. For example, in a one-step process, a user maydepress a needle sleeve against their body in order to cause injectionof a medicament. Other devices may require a multi-step activation of anautomated function. For example, a user may be required to depress abutton and retract a needle shield in order to cause injection.

In addition, activation of one automated function may activate one ormore subsequent automated functions, thereby forming an activationsequence. For example, activation of a first automated function mayactivate at least two of needle insertion, medicament injection, andneedle retraction. Some devices may also require a specific sequence ofsteps to cause the one or more automated functions to occur. Otherdevices may operate with a sequence of independent steps.

Some delivery devices can include one or more functions of a safetysyringe, pen-injector, or auto-injector. For example, a delivery devicecould include a mechanical energy source configured to automaticallyinject a medicament (as typically found in an auto-injector) and a dosesetting mechanism (as typically found in a pen-injector).

According to some embodiments of the present disclosure, an exemplarydrug delivery device 10 is shown in FIGS. 1A & 1B. Device 10, asdescribed above, is configured to inject a medicament into a patient'sbody. Device 10 includes a main body 11 which typically contains areservoir containing the medicament to be injected (e.g., a syringe) andthe components required to facilitate one or more steps of the deliveryprocess. Device 10 can also include a cap assembly 12 that can bedetachably mounted to the main body 11. Typically a user must remove cap12 from main body 11 before device 10 can be operated.

As shown, main body 11 is substantially cylindrical and has asubstantially constant diameter along the longitudinal axis X. The mainbody 11 has a distal region 120 and a proximal region 121. The term“distal” refers to a location that is relatively closer to a site ofinjection, and the term “proximal” refers to a location that isrelatively further away from the injection site.

Device 10 can also include a needle sleeve 24 coupled to main body 11 topermit movement of sleeve 24 relative to main body 11. For example,sleeve 24 can move in a longitudinal direction parallel to longitudinalaxis X. Specifically, movement of sleeve 24 in a proximal direction canpermit a needle 17 to extend from distal region 120 of main body 11.

Insertion of needle 17 can occur via several mechanisms. For example,needle 17 may be fixedly located relative to main body 11 and initiallybe located within an extended needle sleeve 24. Proximal movement ofsleeve 24 by placing a distal end of sleeve 24 against a patient's bodyand moving main body 11 in a distal direction will uncover the distalend of needle 17. Such relative movement allows the distal end of needle17 to extend into the patient's body. Such insertion is termed “manual”insertion as needle 17 is manually inserted via the patient's manualmovement of main body 11 relative to sleeve 24.

Another form of insertion is “automated,” whereby needle 17 movesrelative to main body 11. Such insertion can be triggered by movement ofsleeve 24 or by another form of activation, such as, for example, abutton 122. As shown in FIGS. 1A & 1B, button 122 is located at aproximal end of main body 11. However, in other embodiments, button 122could be located on a side of main body 11.

Other manual or automated features can include drug injection or needleretraction, or both. Injection is the process by which a bung or piston123 is moved from a proximal location within a syringe (not shown) to amore distal location within the syringe in order to force a medicamentfrom the syringe through needle 17. In some embodiments, a drive spring(not shown) is under compression before device 10 is activated. Aproximal end of the drive spring can be fixed within proximal region 121of main body 11, and a distal end of the drive spring can be configuredto apply a compressive force to a proximal surface of piston 123.Following activation, at least part of the energy stored in the drivespring can be applied to the proximal surface of piston 123. Thiscompressive force can act on piston 123 to move it in a distaldirection. Such distal movement acts to compress the liquid medicamentwithin the syringe, forcing it out of needle 17.

Following injection, needle 17 can be retracted within sleeve 24 or mainbody 11. Retraction can occur when sleeve 24 moves distally as a userremoves device 10 from a patient's body. This can occur as needle 17remains fixedly located relative to main body 11. Once a distal end ofsleeve 24 has moved past a distal end of needle 17, and needle 17 iscovered, sleeve 24 can be locked. Such locking can include locking anyproximal movement of sleeve 24 relative to main body 11.

Another form of needle retraction can occur if needle 17 is movedrelative to main body 11. Such movement can occur if the syringe withinmain body 11 is moved in a proximal direction relative to main body 11.This proximal movement can be achieved by using a retraction spring (notshown), located in distal region 120. A compressed retraction spring,when activated, can supply sufficient force to the syringe to move it ina proximal direction. Following sufficient retraction, any relativemovement between needle 17 and main body 11 can be locked with a lockingmechanism. In addition, button 122 or other components of device 10 canbe locked as required.

FIG. 2A shows a side-on cross-section of an auto-injector device 10according to a first embodiment of the disclosure. The device 10comprises a generally cylindrical main body 11 and a generallycylindrical cap 12.

The device 10 also comprises a tubular needle sleeve 24 that fits insidethe main body 11 and is arranged to slide axially with respect to themain body 11. The needle sleeve 24 is a protective sleeve that preventsunwanted exposure of the needle 17. The needle sleeve 24 has a similarshape to the main body and is hollow and generally cylindrical.

The cap 12 has an end wall and a curved side wall and a tubular wall 12a extending from the end wall containing a needle shield 12 c. Theneedle shield 12 c protects a distal end of the needle 17 duringstorage. The needle shield 12 c acts to seal the needle 17. There may beprovided a press fit, form fit or adhesive bond between the needleshield 12 c and the tubular wall 12 a.

The needle shield material can be an elastomer like known needle shieldsfor syringes for auto injectors. The needle shield can also be made outof thermoplastic elastomer (TPE) which may be 2K injection moulded intothe cap 12.

The needle shield is fixed to the cap regarding movement in an axialdirection, so that the needle shield 12 c is removed when the cap isremoved.

The cap 12 fits over the needle sleeve 24. The cap 12 is movable axiallywith respect to the main body 11.

The device 10 comprises a cartridge 19 which is held in place by acartridge holder 20. The cartridge holder 20 and cartridge 19 areconnected and fixed relative to the main body 11 of the device 10. Thecartridge 19 may be provided to a user separately to the device 10. Theuser may insert the cartridge 19 into the device 10.

The device 10 comprises a needle 17 which is held towards the proximalend thereof by a needle holder 18. The distal end of the needle 17 iscovered by the tubular member 12 a of the cap 12. The needle holder 18which holds the needle 17 is axially movable relative to the main body11 and the cartridge 19.

The cartridge 19 has a cartridge body 21, a neck 22 and a head 23. Thehead 23 is wider than the neck 22, thereby forming a flanged end. Theneck 22 and head 23 contain a passage allowing medicament to passtherethrough as well as to receive the needle 17 once inserted. The head23 is provided with a penetrable barrier such as a septum 23 a to closeoff the passage and to seal the contents of the medicament cartridge 19.The cartridge body 21, neck 22 and head 23 may be generally cylindricalin shape. However, alternative shapes may be employed. The cup-shapedportion 18 a is shaped to engage with the head 23 of the cartridge 19.

The cartridge holder 20 is generally tubular and is coaxial with respectto the main body 11. The main wall of the cartridge holder 20 extendsaround the body 21 of the cartridge 19 and extends towards the distalend of the device 10 so that it surrounds the head 23 of the cartridge19, the needle holder 18 and a proximal end portion of the tubularmember 12 a of the cap 12. The cartridge holder 20 has a diametergreater than that of the cartridge 19 and needle holder 18. Thecartridge holder 20 has ribs 25 extending inwardly from the main wall tosupport the cartridge 19 along the length of the cartridge 19.Alternatively, the cartridge holder 20 has a diameter approximatelyequal to that of the cartridge 19 so that a frictional fit is providedbetween the cartridge 19 and the cartridge holder 20 so that the ribsare not necessary. The cartridge holder 20 has a diameter approximatelyequal to that of the tubular member 12 a so that a frictional fit isachieved when the cap 12 is attached to the rest of the device 10, asshown in FIG. 2A.

The cartridge holder 20 has a guide element 20 a such as a pin extendingfrom the inner surface of the main wall of the cartridge holder 20. Theguide element 20 a engages with a slotted link 12 b which is a grooveprovided in the outer surface of the tubular member 12 a of the cap 12.The slotted link 12 b defines a path followed by the guide element 20 aas the cap 12 is rotated by the user and as the cap is pulled away fromthe main body.

FIG. 2B is a projection of the path defined by the slotted link 12 bonto a two-dimensional surface. The slotted link 12 b is generallyhooked shaped in this projection. The curved portion shown in FIG. 2Bdefines the path taken by the guide element 20 a as the user rotates thecap 12. The curved path defined by the slotted link varies axially aswell as running circumferentially around the tubular member 12 a.Therefore movement of the fixed guide element 20 a along the pathdefined by the slotted link results in axial movement of the cap 12 asthe cap 12 is rotated relative to the main body 11.

The straight portion of the slotted link 12 b defines the path taken bythe guide element 20 a as the user pulls the cap 12 from the main body11 subsequent to rotation of the cap 12 and the attachment of the needleholder 18 to the medicament cartridge 19. The slotted link 12 b preventsdetachment of the cap 12 before the cap has been rotated sufficiently toensure attachment of the needle holder 18 to the medicament cartridge19.

The needle holder 18 which holds the needle 17 is axially movablerelative to the main body 11 and the cartridge 19. The needle holder hasa generally cup-shaped portion 18 a and a passage through which theneedle 17 passes. The cup-shaped portion 18 a is shaped to engage withthe head 23 of the cartridge 19. The cup-shaped portion 18 a comprises alip 18 b which serves to clip onto the head 23 to prevent detachment ofthe needle holder 18 from the cartridge 19 subsequent to attachment ofthe needle holder 18 to the cartridge 19. Both ends of the needle 17 aresharp. The proximal end is sufficiently sharp to enable the needle 17 topenetrate the septum 23 a of the medicament cartridge 19. The distal endof the needle 17 is sufficiently sharp to allow the needle to penetratethe patient's skin.

FIG. 3A shows the device 10 as the user rotates the cap 12. The guideelement 20 a moves along a curved portion of the path defined by theslotted link 12 b. In FIG. 3, the guide element 20 a is located in thepart of the slotted link 12 b furthest away from the proximal end of thetubular member 12 a. Since the position of the guide element 20 a isfixed axially with respect to the main body 11 and medicament cartridge19 and cap 12 are axially movable with respect to the main body 11 andmedicament cartridge 19, the rotation of the cap 12 from the positionshown in FIGS. 2A and 2B leads to an axial movement of the cap 12towards the medicament cartridge 19. The tubular member 12 a abuts theneedle holder 18 thereby causing axial movement of the needle holdertowards the medicament cartridge 19.

As shown in FIG. 3A, the needle 17 pierces the septum 23 a of themedicament cartridge 19, thereby establishing a passage for themedicament to flow from the medicament cartridge 19 to the distal end ofthe needle 17.

After moving axially towards the medicament cartridge, the cup-shapedpart 18 a of the needle holder 18 fits over the head 23 of themedicament cartridge 19. Moreover, the lip 18 b extending around thecup-shaped part 18 a of the needle holder further serves to fix theneedle holder 18 to the medicament cartridge 19. The lip 18 b has atapered leading edge to allow the cup shaped part to fit over the head23.

In alternative embodiments, no lip is provided. The diameter of the cupshaped part 18 a and the diameter of the head 23 of the medicamentcartridge 19 can be arranged to ensure a close frictional fit betweenthe needle holder 18 and the medicament cartridge 19.

However, once the needle holder 18 is fitted to the medicament cartridge19, axial movement of the needle holder away, and separation from, themedicament cartridge 19 is prevented by the lip or the frictional fit.

As the cap 12 is rotated beyond the position shown in FIG. 3A, the guideelement 20 a is guided along the curved portion of the slotted link 12 bbetween the guide element 20 a position shown in FIG. 3B and the axiallystraight portion of the path. Because of the direction of the curve ofthe slotted link, rotation of the cap at this stage causes the cap 12 tomove axially away from the needle holder 18 and the medicament cartridge19.

FIGS. 4A and 4B show the device 10 as the cap 12 is removed. The guideelement 20 a reaches the axially straight portion of the slotted link 12b. The cap 12 can no longer be rotated because of the axial direction ofthe slotted link 12 b. The user pulls the cap 12 away from the main body11 in the distal direction.

Once the cap 12 has been removed, the user may commence the injection.The distal end of the device 10 is held against the patient's injectionsite and the device actuated.

In some embodiments, as shown in FIG. 5, the slotted link may 12 b mayhave a narrowed portion 30 that is narrower than the rest of the slottedlink 12 b. This helps to prevent accidental rotation of the cap 12 sothat the needle 17 is not inserted into the cartridge 19 prematurely.

The terms “drug” or “medicament” are used synonymously herein anddescribe a pharmaceutical formulation containing one or more activepharmaceutical ingredients or pharmaceutically acceptable salts orsolvates thereof, and optionally a pharmaceutically acceptable carrier.An active pharmaceutical ingredient (“API”), in the broadest terms, is achemical structure that has a biological effect on humans or animals. Inpharmacology, a drug or medicament is used in the treatment, cure,prevention, or diagnosis of disease or used to otherwise enhancephysical or mental well-being. A drug or medicament may be used for alimited duration, or on a regular basis for chronic disorders.

As described below, a drug or medicament can include at least one API,or combinations thereof, in various types of formulations, for thetreatment of one or more diseases. Examples of API may include smallmolecules having a molecular weight of 500 Da or less; polypeptides,peptides and proteins (e.g., hormones, growth factors, antibodies,antibody fragments, and enzymes); carbohydrates and polysaccharides; andnucleic acids, double or single stranded DNA (including naked and cDNA),RNA, antisense nucleic acids such as antisense DNA and RNA, smallinterfering RNA (siRNA), ribozymes, genes, and oligonucleotides. Nucleicacids may be incorporated into molecular delivery systems such asvectors, plasmids, or liposomes. Mixtures of one or more drugs are alsocontemplated.

The term “drug delivery device” shall encompass any type of device orsystem configured to dispense a drug or medicament into a human oranimal body. Without limitation, a drug delivery device may be aninjection device (e.g., syringe, pen injector, auto injector,large-volume device, pump, perfusion system, or other device configuredfor intraocular, subcutaneous, intramuscular, or intravasculardelivery), skin patch (e.g., osmotic, chemical, micro-needle), inhaler(e.g., nasal or pulmonary), an implantable device (e.g., drug- orAPI-coated stent, capsule), or a feeding system for thegastro-intestinal tract. The presently described drugs may beparticularly useful with injection devices that include a needle, e.g.,a hypodermic needle for example having a Gauge number of 24 or higher.

The drug or medicament may be contained in a primary package or “drugcontainer” adapted for use with a drug delivery device. The drugcontainer may be, e.g., a cartridge, syringe, reservoir, or other solidor flexible vessel configured to provide a suitable chamber for storage(e.g., short- or long-term storage) of one or more drugs. For example,in some instances, the chamber may be designed to store a drug for atleast one day (e.g., 1 to at least 30 days). In some instances, thechamber may be designed to store a drug for about 1 month to about 2years. Storage may occur at room temperature (e.g., about 20° C.), orrefrigerated temperatures (e.g., from about −4° C. to about 4° C.). Insome instances, the drug container may be or may include a dual-chambercartridge configured to store two or more components of thepharmaceutical formulation to-be-administered (e.g., an API and adiluent, or two different drugs) separately, one in each chamber. Insuch instances, the two chambers of the dual-chamber cartridge may beconfigured to allow mixing between the two or more components prior toand/or during dispensing into the human or animal body. For example, thetwo chambers may be configured such that they are in fluid communicationwith each other (e.g., by way of a conduit between the two chambers) andallow mixing of the two components when desired by a user prior todispensing. Alternatively or in addition, the two chambers may beconfigured to allow mixing as the components are being dispensed intothe human or animal body.

The drugs or medicaments contained in the drug delivery devices asdescribed herein can be used for the treatment and/or prophylaxis ofmany different types of medical disorders. Examples of disordersinclude, e.g., diabetes mellitus or complications associated withdiabetes mellitus such as diabetic retinopathy, thromboembolismdisorders such as deep vein or pulmonary thromboembolism. Furtherexamples of disorders are acute coronary syndrome (ACS), angina,myocardial infarction, cancer, macular degeneration, inflammation, hayfever, atherosclerosis and/or rheumatoid arthritis. Examples of APIs anddrugs are those as described in handbooks such as Rote Liste 2014, forexample, without limitation, main groups 12 (anti-diabetic drugs) or 86(oncology drugs), and Merck Index, 15th edition.

Examples of APIs for the treatment and/or prophylaxis of type 1 or type2 diabetes mellitus or complications associated with type 1 or type 2diabetes mellitus include an insulin, e.g., human insulin, or a humaninsulin analogue or derivative, a glucagon-like peptide (GLP-1), GLP-1analogues or GLP-1 receptor agonists, or an analogue or derivativethereof, a dipeptidyl peptidase-4 (DPP4) inhibitor, or apharmaceutically acceptable salt or solvate thereof, or any mixturethereof. As used herein, the terms “analogue” and “derivative” refer toany substance which is sufficiently structurally similar to the originalsubstance so as to have substantially similar functionality or activity(e.g., therapeutic effectiveness). In particular, the term “analogue”refers to a polypeptide which has a molecular structure which formallycan be derived from the structure of a naturally occurring peptide, forexample that of human insulin, by deleting and/or exchanging at leastone amino acid residue occurring in the naturally occurring peptideand/or by adding at least one amino acid residue. The added and/orexchanged amino acid residue can either be codable amino acid residuesor other naturally occurring residues or purely synthetic amino acidresidues. Insulin analogues are also referred to as “insulin receptorligands”. In particular, the term “derivative” refers to a polypeptidewhich has a molecular structure which formally can be derived from thestructure of a naturally occurring peptide, for example that of humaninsulin, in which one or more organic substituent (e.g. a fatty acid) isbound to one or more of the amino acids. Optionally, one or more aminoacids occurring in the naturally occurring peptide may have been deletedand/or replaced by other amino acids, including non-codeable aminoacids, or amino acids, including non-codeable, have been added to thenaturally occurring peptide.

Examples of insulin analogues are Gly(A21), Arg(B31), Arg(B32) humaninsulin (insulin glargine); Lys(B3), Glu(B29) human insulin (insulinglulisine); Lys(B28), Pro(B29) human insulin (insulin lispro); Asp(B28)human insulin (insulin aspart); human insulin, wherein proline inposition B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein inposition B29 Lys may be replaced by Pro; Ala(B26) human insulin;Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) humaninsulin.

Examples of insulin derivatives are, for example,B29-N-myristoyl-des(B30) human insulin, Lys(B29)(N-tetradecanoyl)-des(B30) human insulin (insulin detemir, Levemir®);B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin;B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 humaninsulin; B28-N-palmitoyl-LysB28ProB29 human insulin;B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30human insulin; B29-N—(N-palmitoyl-gamma-glutamyl)-des(B30) humaninsulin, B29-N-omega-carboxypentadecanoyl-gamma-L-glutamyl-des(B30)human insulin (insulin degludec, Tresiba®);B29-N—(N-lithocholyl-gamma-glutamyl)-des(B30) human insulin;B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N-(ω-carboxyheptadecanoyl) human insulin.

Examples of GLP-1, GLP-1 analogues and GLP-1 receptor agonists are, forexample, Lixisenatide (Lyxumia®, Exenatide (Exendin-4, Byetta®,Bydureon®, a 39 amino acid peptide which is produced by the salivaryglands of the Gila monster), Liraglutide (Victoza®), Semaglutide,Taspoglutide, Albiglutide (Syncria®), Dulaglutide (Trulicity®),rExendin-4, CJC-1134-PC, PB-1023, TTP-054, Langlenatide/HM-11260C, CM-3,GLP-1 Eligen, ORMD-0901, NN-9924, NN-9926, NN-9927, Nodexen,Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, GSK-2374697, DA-3091, MAR-701,MAR709, ZP-2929, ZP-3022, TT-401, BHM-034. MOD-6030, CAM-2036, DA-15864,ARI-2651, ARI-2255, Exenatide-XTEN and Glucagon-Xten.

An example of an oligonucleotide is, for example: mipomersen sodium(Kynamro®), a cholesterol-reducing antisense therapeutic for thetreatment of familial hypercholesterolemia.

Examples of DPP4 inhibitors are Vildagliptin, Sitagliptin, Denagliptin,Saxagliptin, Berberine.

Examples of hormones include hypophysis hormones or hypothalamushormones or regulatory active peptides and their antagonists, such asGonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin),Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin,Triptorelin, Leuprorelin, Buserelin, Nafarelin, and Goserelin.

Examples of polysaccharides include a glucosaminoglycane, a hyaluronicacid, a heparin, a low molecular weight heparin or an ultra-lowmolecular weight heparin or a derivative thereof, or a sulphatedpolysaccharide, e.g. a poly-sulphated form of the above-mentionedpolysaccharides, and/or a pharmaceutically acceptable salt thereof. Anexample of a pharmaceutically acceptable salt of a poly-sulphated lowmolecular weight heparin is enoxaparin sodium. An example of ahyaluronic acid derivative is Hylan G-F 20 (Synvisc®), a sodiumhyaluronate.

The term “antibody”, as used herein, refers to an immunoglobulinmolecule or an antigen-binding portion thereof. Examples ofantigen-binding portions of immunoglobulin molecules include F(ab) andF(ab′)₂ fragments, which retain the ability to bind antigens. Theantibody can be polyclonal, monoclonal, recombinant, chimeric,de-immunized or humanized, fully human, non-human, (e.g., murine), orsingle chain antibody. In some embodiments, the antibody has effectorfunction and can fix a complement. In some embodiments, the antibody hasreduced or no ability to bind an Fc receptor. For example, the antibodycan be an isotype or subtype, an antibody fragment or mutant, which doesnot support binding to an Fc receptor, e.g., it has a mutagenized ordeleted Fc receptor binding region. The term antibody also includes anantigen-binding molecule based on tetravalent bispecific tandemimmunoglobulins (TBTI) and/or a dual variable region antibody-likebinding protein having cross-over binding region orientation (CODV).

The terms “fragment” or “antibody fragment” refer to a polypeptidederived from an antibody polypeptide molecule (e.g., an antibody heavyand/or light chain polypeptide) that does not comprise a full-lengthantibody polypeptide, but that still comprises at least a portion of afull-length antibody polypeptide that is capable of binding to anantigen. Antibody fragments can comprise a cleaved portion of a fulllength antibody polypeptide, although the term is not limited to suchcleaved fragments. Antibody fragments that are useful in the presentdisclosure include, for example, Fab fragments, F(ab′)2 fragments, scFv(single-chain Fv) fragments, linear antibodies, monospecific ormultispecific antibody fragments such as bispecific, trispecific,tetraspecific and multispecific antibodies (e.g., diabodies, triabodies,tetrabodies), monovalent or multivalent antibody fragments such asbivalent, trivalent, tetravalent and multivalent antibodies, minibodies,chelating recombinant antibodies, tribodies or bibodies, intrabodies,nanobodies, small modular immunopharmaceuticals (SMIP), binding-domainimmunoglobulin fusion proteins, camelized antibodies, and VHH containingantibodies. Additional examples of antigen-binding antibody fragmentsare known in the art.

The terms “Complementarity-determining region” or “CDR” refer to shortpolypeptide sequences within the variable region of both heavy and lightchain polypeptides that are primarily responsible for mediating specificantigen recognition. The term “framework region” refers to amino acidsequences within the variable region of both heavy and light chainpolypeptides that are not CDR sequences, and are primarily responsiblefor maintaining correct positioning of the CDR sequences to permitantigen binding. Although the framework regions themselves typically donot directly participate in antigen binding, as is known in the art,certain residues within the framework regions of certain antibodies candirectly participate in antigen binding or can affect the ability of oneor more amino acids in CDRs to interact with antigen.

Examples of antibodies are anti PCSK-9 mAb (e.g., Alirocumab), anti IL-6mAb (e.g., Sarilumab), and anti IL-4 mAb (e.g., Dupilumab).

Pharmaceutically acceptable salts of any API described herein are alsocontemplated for use in a drug or medicament in a drug delivery device.Pharmaceutically acceptable salts are for example acid addition saltsand basic salts.

Those of skill in the art will understand that modifications (additionsand/or removals) of various components of the APIs, formulations,apparatuses, methods, systems and embodiments described herein may bemade without departing from the full scope and spirit of the presentinvention, which encompass such modifications and any and allequivalents thereof.

1. A medicament injection device comprising: a main body arranged toreceive a medicament cartridge; a needle carrier carrying a needle,wherein the needle carrier is axially movable with respect to the mainbody; a rotatable cap at a distal end of the medicament injectiondevice, wherein the rotatable cap is removably coupled to the needlecarrier; and a releasable arrangement between the main body and therotatable cap comprising a guide element and a slotted link, wherein theslotted link is arranged to cause the guide element to follow apredefined path at least partly in an axial direction during rotationalmovement of the rotatable cap, thereby causing the needle carrier tomove axially towards a proximal end of the device as the rotatable capis rotated up to a predefined point, wherein the main body comprises amedicament cartridge holder comprising the guide element dependingtherefrom for engagement with the rotatable cap.
 2. The device of claim1, wherein the rotatable cap comprises a tubular element, the outersurface of the tubular element having the slotted link arranged thereonto receive the guide element.
 3. The device of claim 2, wherein thetubular element contains a needle shield.
 4. The device of claim 1,wherein the slotted link is configured to cause the rotatable cap tomove axially in a distal axial direction when the rotatable cap isrotated beyond the predefined point.
 5. The device of claim 1, whereinthe slotted link comprises a portion that is relatively narrow incomparison to a remainder of the slotted link.
 6. The device of claim 1,wherein the slotted link comprises an axially straight part.
 7. Thedevice of claim 1, wherein the needle holder is arranged to become fixedto the medicament cartridge after axial movement thereof in a proximaldirection.
 8. The device of claim 7, wherein the needle holder comprisesa lip arranged to cooperate with a head of the medicament cartridge. 9.The device of claim 7, wherein the needle holder is dimensioned to forma frictional fit with the head of the medicament cartridge.
 10. Thedevice of claim 1, wherein the medicament cartridge holder containsmedicament cartridge, the medicament cartridge having a penetrablebarrier at a distal end thereof, and axial movement of the needlecarrier towards the proximal end causes the needle to pierce thepenetrable barrier of the medicament cartridge.
 11. The device of claim10, wherein the medicament cartridge contains a medicament.
 12. Thedevice of claim 1, wherein the medicament infection device is anauto-injector.
 13. A method of operating a medicament injection devicehaving a rotatable cap, the method comprising: rotating the rotatablecap, thereby causing a releasable arrangement between a main body andthe rotatable cap comprising a guide element and a slotted link tocooperate to cause a needle to move axially in a proximal direction andto penetrate a separable barrier of a medicament cartridge, wherein themain body comprises a medicament cartridge holder comprising the guideelement depending therefrom for engagement with the rotatable cap. 14.The method of claim 13, wherein further rotation of the rotatable capcauses the rotatable cap to move axially in a distal direction.